In vivo imaging agents targeting Tau aggregates

描述（由申请人提供）：阿尔茨海默病（AD）是一种脑神经退行性疾病，症状包括痴呆、认知障碍和记忆丧失。这种疾病具有非常重要的医学意义，因为它正在影响数百万老年人，发病率不断增加。淀粉样蛋白聚集体（A斑）和tau蛋白（缠结）在大脑中的聚集和积累是这种潜伏疾病的独特标志。两者都是含有平行半折叠结构的蛋白质聚集体。聚集体可能与脑细胞神经变性的病理生理学有关。目前，早期评估临床症状诊断AD往往是困难和不可靠的。因此，迫切需要体内成像剂，其可以特异性地显示脑中缠结和斑块的位置和密度。该项目的目的是开发潜在的F-18和I-123标记的诊断成像剂，分别使用正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）特异性检测大脑中的缠结（tau聚集体）。对AD的生物标志物tau（缠结）进行成像可能会提高对疾病进展的理解，并且可能有助于监测针对脑细胞中过度磷酸化tau形成的药物治疗。基于我们实验室最近在开发A？斑块靶向成像剂方面的成功，我们相信扩展到开发新的缠结选择性探针的领域是可行的。通常认为皮质基底节变性（CBD）或进行性核上性麻痹（PSP）患者的脑样品主要含有缠结（主要由tau聚集体组成）。利用CBD和PSP的死后脑组织样品进行匀浆结合试验和组织切片标记，我们希望选择性地检测tau结合。提出了三个具体目标：（一）。tau聚集体特异性结合的体外结合测定。II）。新化合物的合成。III）。脑切片的体外放射自显影。IV）。将标记所选化合物，并使用正常小鼠通过体内生物分布研究进一步评价。提出的具体目标是创新的，精心制作，以满足选择tau特异性成像剂的严格要求。我们相信，tau选择性成像剂可以成功开发，它们将作为早期检测AD的诊断工具满足未满足的需求。阿尔茨海默病和其他Tau病是脑的神经退行性疾病。在我们的老龄化社会中，它们正成为日益重要的医疗问题。为了解决它们带来的巨大的未来医疗负担，我们现在需要找到有效的诊断工具和治疗神经退行性疾病的方法。这些疾病最显著的解剖学特征是存在淀粉样蛋白（A）斑块和神经纤维缠结，其中含有高度磷酸化的Tau蛋白。本项目的目的是开发F和I标记的分子成像剂，可以选择性地检测18 123 Tau聚集体在活的人脑中。与PET（正电子发射断层扫描）或SPECT（单光子计算机断层扫描）结合，这些试剂将是至关重要的工具，其将能够可视化和量化Tau聚集体在患有神经退行性疾病的患者的脑中的积累。该项目的关键目标是找到对Tau 18 123聚集体具有高结合亲和力的F或I化合物，其可以在活体人脑中传递与Tau聚集体相关的足够信号。开发这些显像剂的潜在益处包括：a）更精确地诊断和监测有症状患者中AD或Tau病的进展; B）改善AD或其他Tau病相关病症之前的无症状老年患者的风险分层; c）更好地理解Tau聚集体积累在MCI和AD患者进展中的作用; d）催化抗Tau疗法的开发。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease of the brain, symptoms include dementia, cognitive impairment and memory loss. The disease has a very significant medical importance because it is affecting millions of older population with increasing incidence. Formation and accumulation of aggregates of ¿-amyloid aggregates (A¿ plaques) and tau (tangles) in the brain are distinctive hallmarks of this insidious disease. Both are protein aggregates that contain parallel ¿-sheet structures. The aggregates are likely to be linked to the patho-physiology of neurodegeneration of brain cells. Currently, early appraisal of clinical symptoms for diagnosis of AD is often difficult and unreliable. Therefore, there is an urgent need for in vivo imaging agents, which can specifically demonstrate the location and density of tangles and plaques in the brain. The objective of this project is to develop potential F-18 and I-123 labeled diagnostic imaging agents, which specifically detect tangles (tau aggregates) in the brain using positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively. Imaging tau (tangles), a biomarker for AD, may lead to improve understanding of disease progression and it may potentially be useful for monitoring drug treatment targeting the formation of hyperphosphorylated tau in the brain cells. Based on recent success from our laboratory on developing A¿ plaque-targeting imaging agents, we believe that it is feasible to expand into the area of developing new selective probes for tangles. It is generally accepted that brain samples of corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) patients contain predominately tangles (consisting mainly tau aggregates). Using postmortem brain tissue samples of CBD and PSP for homogenate binding assay and tissue section labeling, we hope to selectively detect tau binding. Three specific aims are proposed: I). In vitro binding assay for specific binding of tau aggregates. II). Synthesis of new compounds. III). In vitro autoradiography of brain sections. IV). Selected compounds will be labeled and evaluated further by in vivo biodistribution study using normal mice. The proposed specific aims are innovative and carefully crafted to meet the stringent requirements for selecting tau-specific imaging agents. We believe that tau-selective imaging agents can be successfully developed and they will serve an unmet need as diagnostic tools for early detection of AD. Alzheimer's disease and other Tauopathies are neurodegenerative diseases of the brain. They are becoming increasingly significant medical problems in our aging society. In order to address the enormous future healthcare burdens that they pose, we need to find effective diagnostic tools and therapeutics for neurodegenerative diseases now. The most significant anatomical hallmarks of these diseases are the presence of ¿-amyloid (A¿) plaques, and neurofibrillary tangles, which contain highly phosphorylated Tau proteins. The objective of this project is to develop F and I labeled molecular imaging agents that can selectively detect 18 123 Tau aggregates in the living human brain. In conjunction with PET (positron emission tomography) or SPECT (single photon computed tomography) these agents will be critically important tools that will be able to visualize and quantify the accumulation of Tau aggregates in the brain of patients with neurodegenerative diseases. The critical objective of this project is to find a F or I compound with a high binding affinity to Tau 18 123 aggregates which can deliver sufficient signal correlated with Tau aggregates in the living human brain. The potential benefits of developing these imaging agents include: a) More precise diagnosis and monitoring of the progression of AD or Tauopathies in symptomatic patients; b) Improved risk stratification of asymptomatic elderly patients prior to AD or other Tauopathy related disorders; c) Better understanding the role of Tau aggregate accumulation in progression of MCI and AD patients; d) Catalyzation of the development of anti-Tau therapies.